ES2972282T3 - Migraine treatment - Google Patents

Abstract

16α,17α-epoxy-10β-hydroxyestr-4-en-3-one is useful in the treatment of migraine by nasal administration. (Automatic translation with Google Translate, no legal value)

Description

DESCRIPTION

Migraine treatment

Technical field

This invention relates to the treatment of migraine.

Technical background

Migraine

According to Burstein et al., "Migraine: Multiple Processes, Complex Pathophysiology", J. Neuroscience, vol. 35(17), pp. 6619-6629 (2015), migraine is a recurrent headache disorder that affects approximately 15% of the population during the formative and most productive periods of their lives, between the ages of 22 and 55. It often begins in childhood, particularly around puberty, and affects women more than men (3:1 female-to-male ratio). It tends to run in families and, as such, is considered a genetic disorder. According to the Merck Manual, Professional Version, online, https://www.merckmanuals.com/professional/neurologic-disorders/headache/migraine, evidence-based assessment of veterans of the Iraq and Afghanistan conflicts suggests that migraine may frequently develop after mild head trauma.

In some cases, the migraine begins without warning signs and ends with sleep. In other cases, the migraine may be preceded by a premonitory or prodromal phase that may begin up to 3 days before the onset of the migraine, allowing patients to predict the onset of a migraine long before it occurs. Common premonitory symptoms involve the hypothalamus, brainstem, limbic system, and certain cortical areas, and include fatigue; euphoria; depression; irritability/anger; food cravings; constipation; neck stiffness; increased yawning; and/or abnormal sensitivity to light, sound, and smells. The migraine may also be preceded by an aura phase (seen in approximately 25% of migraine patients) that includes a variety of cortically mediated focal neurological symptoms that appear just before and/or during the headache phase. Migraine aura symptoms develop gradually, exhibit excitatory and inhibitory phases, and resolve completely. Positive (gain of function) and negative (loss of function) symptoms can present as flashing lights and scotomas when they affect the visual cortex; paresthesia and numbness of the face and hands when they affect the somatosensory cortex; tremor and unilateral muscle weakness when they affect the motor cortex or basal ganglia; and difficulty saying words (aphasia) when they affect the speech area.

The migraine is usually unilateral, pulsating, worsens with routine physical activity, and can last from a few hours to a few days. As the migraine progresses, it may be accompanied by a variety of autonomic symptoms (nausea, vomiting, nasal/sinus congestion, rhinorrhea, lacrimation, ptosis, yawning, frequent urination and diarrhea), affective symptoms (depression and irritability), cognitive symptoms (attention deficit, difficulty finding words, transient amnesia, and reduced ability to navigate familiar environments) and sensory symptoms (photophobia, phonophobia, osmophobia, muscle tenderness, and cutaneous allodynia).

Fluctuating estrogen levels are a powerful migraine trigger. Many women experience migraine during menarche, severe attacks during menstruation (menstrual migraine), and attacks that worsen during menopause. For most women, migraines decrease during pregnancy, but sometimes worsen during the first or second trimester; They often worsen after childbirth, when estrogen levels decline rapidly. Oral contraceptives and other hormonal therapies occasionally trigger or worsen migraine and have been associated with stroke in women who have migraine with aura.

Patients with episodic migraine (EM), headaches no more than fourteen days a month, may develop chronic migraine. Chronic migraine (CM) is diagnosed in patients who, on average, have at least fifteen headache days per month, with headaches on at least eight of those days with migraine characteristics, for at least three months. This headache disorder used to be called combined or mixed headache because it had characteristics of both a migraine and a tension-type headache. These CM headaches often develop in patients who abuse medications for the acute treatment of ME headaches.

Based on current knowledge, brain regions related to pain modulation and processing include the prefrontal cortex, cingulate cortex, insular cortex, thalamus, basal ganglia, cerebellum, and periaqueductal gray matter. Recent high-resolution magnetic resonance imaging (MRI) studies report activation and increased functional connectivity of the hypothalamus and amygdala in very early stages of migraine episodes and propose the hypothalamus as the site of attack generation of migraine. Denuelle et al.,"Hypothalamic Activation in Spontaneous Migraine Attacks", Headache, vol. 47(1), pp.

1418-1426 (2007), report on a positron imaging tomography (PET) study using H215O of seven migraine patients, studied during a spontaneous migraine attack, after headache relief with sumatriptan, and during an interval without attacks 15 to 60 days after the measured attack; and significant activation was seen in the midbrain, pons, and hypothalamus during headache, persisting after headache relief. Chenet al.,"Altered functional connectivity of amygdala underlying the neuromechanism of migraine pathogenesis", J. Headache Pain, vol. 18(7), DOI 10.1186/s 10194-017-0722-5 (2017), report magnetic resonance studies, including functional magnetic resonance imaging (fMRI) in normal controls (CN) and patients with ME and CM; and observed greater functional connectivity of the left amygdala in the ME and decreased functional connectivity of the right amygdala in the CM relative to CN, and greater functional connectivity of the bilateral amygdala in the CM relative to the ME. They concluded that altered functional connectivity of the amygdala demonstrated that the neurolimbic pain network contributes to the pathogenesis of ME and the chronification of CM. Leeet al.,"Increased connectivity of pain matrix in chronic migraine: a resting-state functional MRI study", J. Headache Pain, vol. 20(29), DOI 10.1186/s10194-019-0986-z (2019), report an fMRI study of patients with ME and CM; and conclude that patients with CM have stronger functional connectivity in the pain matrix than patients with ME, that the pain matrix is functionally correlated with the hypothalamus and the dorsal raphe nucleus, and that the functional alteration of the matrix of pain may play a role in the chronification of migraine. Mayet al.,"Hypothalamic regulation of headache and migraine", Cephalalgia, vol. 39(13), pp. 1710-1719 (2019), discuss recent work in the field and "review the clinical and neuroscientific evidence that places the hypothalamus at the center of scientific attention when analyzing seizure generation."

For some patients, migraine is a tolerable and infrequent discomfort. For others, it is a devastating disorder that causes frequent periods of disability, loss of productivity, and severely impaired quality of life.

Pharmacological treatment of migraine

Treatment of migraine may include preventive therapy aimed at reducing the frequency and/or severity of migraine attacks (i.e., inhibiting the onset of the migraine, or one or more of its symptoms, or making migraines or symptoms are less intense when a migraine attack occurs), and acute therapy used to interrupt a migraine attack (inhibit the migraine or its symptoms, and relieve or palliate the migraine or its symptoms, when a migraine attack occurs ).

According to Kahrimanet al.,"Migraine and Tension-Type Headache", Semin. Neurol., vol. 38(6), pp. 608-618 (2018), acute migraine treatments can be separated into three main classes: (1) non-specific analgesics (e.g., paracetamol), (2) migraine-specific analgesics (e.g. , triptans, and ergots) and (3) adjunctive treatment for other associated symptoms (e.g., antiemetics).

The American Headache Society considers acetaminophen, ibuprofen, naproxen, and diclofenac "established as effective for the treatment of acute migraine" and ketorolac as "probably effective"; and considers the antiemetics metoclopramide and prochlorperazine to be "probably effective." Considers triptans and ergots to be "established as effective," although triptans have largely replaced ergots due to the more problematic side effect profile and lower convenience of ergots; but triptans can also cause vasoconstriction and are contraindicated in people with vascular diseases such as coronary artery disease, ischemic stroke, peripheral artery disease, and Raynaud's disease. Finally, it considers butalbital and opioids to be "possibly effective", although they are not recommended for routine use due to the risk of dependence and abuse (see for example, Michael J. Marmuraet al.;Headache 2015; 55:3-20) .

According to "Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults", Neurology, vol. 78(17), pp. 1337-1345 (2012), the American Academy of Neurology and American Headache Society considers the antiepileptic drugs divalproex sodium, valproate sodium, and topiramate to have "established efficacy" as preventive therapy for migraine, but valproates can cause a number of side effects that They include alopecia, digestive complaints, liver dysfunction, thrombocytopenia, tremor and weight gain, and are contraindicated in pregnant women due to the risk of teratogenicity, while topiramate may cause weight loss and adverse effects on the central nervous system. The beta-blockers metoprolol, propranolol, and timolol are also considered to have "established efficacy," but only beta-blockers without intrinsic sympathomimetic activity should be used and all should be avoided in patients with bradycardia, hypotension, diabetes, or asthma. Other beta blockers, atenolol and nadolol, are considered "probably effective." The antidepressants amitriptyline and venlafaxine are also considered "probably effective," but amitriptyline has anticholinergic effects and causes weight gain. Many other drugs in the same and different class have also been tested, but they were considered "possibly effective", lacked adequate data, or even "established not effective" (lamotrigine), "probably not effective" (clomipramine) or "possibly not effective" (various compounds).

Onabotulinumtoxin A (BOTOX® from Allergan) has been approved by the US FDA for the treatment of chronic migraine. A single treatment consists of injections of 0.1 ml (5 units) of onabotulinumtoxin A in 31 different sites in the superficial zones of seven different muscle areas of the head and neck. An initial course of treatment involves two treatments twelve weeks apart and a new treatment is recommended every twelve weeks. According to the American Academy of Neurology practice guidelines, “Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache,” Neurology, vol.

86(19), pp. 1818-1826 (2016), onabotulinumtoxin A "should be offered as a treatment option to patients with chronic migraine to increase the number of headache-free days" and "should be considered to reduce the impact of headache on headache-related quality of life." health", but should not be offered as a treatment for episodic migraine.

As disclosed in the "AHS Consensus Statement: The American Headache Society Position Statement on Integrating New Migraine Treatments Into Clinical Practice," Headache, vol. 59(1), pp. 1-18 (2019), emerging preventive options include humanized monoclonal antibodies against calcitonin gene-related peptide (CGRP), with three US FDA-approved agents: erenumab (targeting the PRGC receptor) and fremanezumab and galcanezumab (targeting the PRGC ligand). All three agents are administered by subcutaneous injection every four weeks, and fremanezumab can also be administered by subcutaneous injection quarterly, using three dosing administrations every four weeks.

Notwithstanding the present agents, there is still a need for an effective and tolerable therapy for migraine.

Nasal and ferine chemosensory receptors

In most species, including humans, neuroepithelial cells in the mucosal lining of the dorsal nasal recess and nasal septum, including the vomeronasal organ ("VNO", a bilateral chemosensory organ found in most vertebrates, including humans) have chemosensory receptors associated with the detection of odors and pheromones (see generally Muller-Schwarze and Silverstein, "Chemical Signals", Plenum Press, New York (1980); Monti-Blochet al.,"Effect of putative pheromones on the electrical activity of the human vomeronasal organ and olfactory epithelium", J. Steroid Biochem. Mol. Biol., vol. 39(4), pp. 573-582, 1991); Monti-Blochet al.,"The Human Vomeronasal System: A Review", Ann. N.Y. Academic Sci., vol. 855, pp. 373-389 (1998)). The axons of the neuroepithelial cells of the nasal chemosensory receptors, including the OVN, have direct oligosynaptic input to the hypothalamus and limbic amygdala of the brain, while the distal processes (microvilli) have chemosensory receptors (Stensaaset al., "Ultrastructure of the human vomeronasal organ", J. Steroid Biochem. Mol. Biol., vol. 39(4), pp. 553-560 (1991)).

The putative human pheromones delivered to the nasal septal area bind to local chemosensory receptors and trigger neural signals that reach the brain inducing physiological and behavioral changes (Grosseret al., "Behavioral and electrophysiological effects of androstadienone, a human pheromone", Psychoneuroendocrinology, vol. 25, pp. 289-299 (2000)). Synthetic analogues of human pheromones called pheromone (odorless substances that bind to nasal chemosensory receptors, including receptors in the VNO) can induce strong physiological, pharmacological and behavioral effects when transported through the air to these receptors through the nostrils. This information is supported by several studies in human volunteers using MRI and PET scans, which show that PPH selectively activates areas of the brain (hypothalamus, limbic system, cingulate gyrus, anterior thalamus and prefrontal cortex) where its physiological and pharmacological effects are integrated. and behavioral. Studies with several pherins have shown that, since the compounds act directly on nasal chemosensory receptors that are connected to the brain by short neuronal circuits, administration of the compounds causes an effect on physiological markers (e.g., responses of the autonomic nervous system and EEG) in a matter of seconds to less than a minute, and an effect on behavior and on markers of neurotransmitter and endocrine metabolites in approximately 10 to 15 minutes.

16a,17a-Epoxy-10p-hydroxyestr-4-en-3-one

U.S. Patent No. 6057439, "Steroids as neurochemical stimulators of the VNO to alleviate symptoms of PMS and anxiety," describes the use of a series of steroidal phentermines for the treatment of premenstrual dysphoric disorder ("PMDD"). , also known as "premenstrual syndrome" or "PMS"). and anxiety by administration to the vomeronasal organ of an individual suffering from those symptoms. 16a,17a-Epoxy-10p-hydroxyestr-4-en-3-one is described in the patent, where it is called 16a,17a-epoxyestr-4-en-10p-ol-3-one. The patent discloses the synthesis of the compound and claims the compound and pharmaceutical compositions containing it to alleviate the symptoms of PMDD. The<e>U.S. patent. No. 6331534, "Steroids as neurochemical stimulators of the VNO to alleviate pain", describes the same steroids to relieve pain by vomeronasal administration. US Patent No. 8431559, "Treatment of hot flashes", describes a synthesis of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one and the use of 16a,17a-epoxy -10p-hydroxyestr-4-en-3-one to relieve hot flashes by vomeronasal administration.

Summary of the invention

In a first aspect, this invention is the treatment of migraine (treatment of individuals suffering from migraine) by nasal administration of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one.

In other aspects, this invention therefore includes:

16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for or for use in the treatment of migraine by nasal administration; and

pharmaceutical formulations and devices containing 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for the treatment of migraine by nasal administration;

16a,17a-epoxy-10p-hydroxyestr-4-en-3-one has particular utility in the treatment of migraine (treatment of individuals suffering from migraine); and is expected to have the following advantages over conventional treatments:

(1) ease of administration while retaining capacity for acute use;

(2) rapid onset of effect, due to direct local delivery of the compound to nasal chemosensory receptors and action accordingly. Current oral anti-migraine agents, like other oral agents in general, may take 30 minutes or more to achieve therapeutic effectiveness;

and

(3) absence of local nasal adverse effects and absence of systemic effects or toxicity, due to the local route of administration, the effect on peripheral (nasal) chemosensory receptors and the demonstrated absence of systemic bioavailability, and the effect on the nervous system central through the activation of short neuronal circuits (oligosynaptic).

Preferred embodiments of this invention are characterized by the specification and features of claims 1 to 15 of this application, as filed.

Detailed description

Definitions

Migraine and its treatment are described in the subsections entitled "Migraine" and "Pharmacological treatment of migraine" of the background of the art.

"Comprising" or "containing" and their grammatical variants are words of inclusion and not of limitation and are intended to specify the presence of components, groups, stages and the like indicated, but not to exclude the presence or addition of other components, groups, stages and the like. Therefore, "comprising" does not mean "consisting of", "consisting substantially of" or "consisting only of"; and, for example, a formulation "comprising" a compound must contain that compound, but may also contain other active ingredients and/or excipients.

"Nasal administration" is administration to human nasal chemosensory receptors, including VNO receptors. In a clinical context, this can be achieved by using a probe specifically designed to deliver 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one virtually alone to the OVN (such a probe also designed to measure the effect on vomeronasal tissue, is described in Monti-Bloch, US Patent No. 5303703, "Combined neuroepithelial sample delivery electrode device and methods of using the same"). More commonly, however, nasal administration comprises administration to the nasal passages in a manner that desirably targets 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one generally toward nasal chemosensory receptors, including VNO receptors, such as by using conventional nasal spray technology commonly used for nasal delivery of steroids for allergies and asthma.

A "therapeutically effective amount" means the amount of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one that, when administered to the nasal chemosensory receptors of an individual suffering from migraine, is sufficient to achieve the treatment of migraine, but the amount is insufficient to have a systemic effect on migraine by absorption into the circulation. "Treatment" or "treating" migraine disorder includes one or more of:

(1) inhibit the occurrence of migraine, or a migraine symptom;

(2) relieve the migraine, or a migraine symptom, when it occurs, and

(3) alleviate migraine symptoms.

16a,17a-Epoxy-10p-hydroxyestr-4-en-3-one and its preparation

The preparation of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one is described in US Patent No. 6057439; and a preparation from the readily commercially available steroid estrone, 3-hydroxyestra-1,3,5(10)-trien-17-one, is described in US Patent No. 8431559.

One skilled in the art will have no difficulty, considering that skill and US Patent Nos. 6057439 and 8431559, in the preparation of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one .

Formulation and administration

16a,17a-epoxy-10p-hydroxyestr-4-en-3-one can be administered nasally by any suitable route. Routes of administration include, but are not limited to, topical applications (e.g., of a nasal gel or cream), nasal spray, powdered nasal spray, aerosol, and the like. Pharmaceutical formulations will generally be formulations designed to deliver the drug across mucous membranes. Suitable formulations for each of these methods of administration can be found, for example, in Gennaro, ed., "Remington: The Science and Practice of Pharmacy", 20 ed., Lippincott Williams & Wilkins, Philadelphia, Pennsylvania, (2003). Typical preferred formulations will be aqueous solutions for nasal spray and will contain 16a,17a-epoxy-10phydroxyestr-4-en-3-one and water, typically also containing one or more pharmaceutically acceptable excipients to increase the aqueous solubility of 16a,17a. -epoxy-10p-hydroxyestr-4-en-3-one, such as alcohols and glycols (for example, ethanol and propylene glycol) and surfactants (for example, polysorbate 80 (polyoxyethylene (20) sorbitan monooleate)), and may also contain one or more pharmaceutically acceptable excipients such as buffers, preservatives (antioxidants, chelating agents, etc.), tonifiers, viscosity enhancers (dextrans, cyclodextrins, polyvinylpyrrolidones, polyethylene glycols, etc.), and the like, such as those known for solutions aqueous for nasal spray. Suitable delivery devices for these formulations are the metered dose nasal spray pumps commonly used for nasal delivery of steroids for allergies and asthma. Several manufacturers produce pumps of this type, for example, Aptar. Liquid volumes should be such that the formulation is delivered efficiently without exceeding the nasal retention volume, and that an excess flows back into the sinuses or drips from the nose, and 100 pl has been considered a convenient volume, although larger or smaller volumes will also be satisfactory (a volume of 50 pl has been tested satisfactorily). Desirably, the aqueous solution formulations and the delivery devices used to deliver them will be chosen to achieve maximum retention of the sprayed formulation within the nasal passages, for example, by choosing them so that the average size of the sprayed droplets is between approximately 30 and 50 micrometers. For powder formulations, a particle size of between about 50 and 100 micrometers is generally considered suitable.

Illustrative aqueous solution formulations include the two formulations discussed in Example 4 below. Another illustrative formulation is the following:

One skilled in the art will have no difficulty, considering that skill and this disclosure, in preparing suitable formulations and delivery systems of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for nasal administration.

A therapeutically effective amount of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one, when administered in a nasal spray formulation of the above type, is about 0.8 to 19.2 pg per administration, preferably from 1.6 to 9.6 pg per administration, for example, approximately 1.6 pg, 3.2 pg or 6.4 pg per administration. For a concentration of 16 mg/l (16 ppm) of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one in the formulation, each administration of 1.6 pg would therefore be equivalent to 100 pl of the formulation, conveniently a single administration of 100 pl in one nostril, each administration of 3.2 pg would be 200 pl of the formulation, conveniently a single administration of 100 pl to each nostril; and each administration of 6.4 pg would be 400 pl of the formulation, conveniently two administrations of 100 pg to each nostril. It is expected that no more than a few percent of this dose will actually reach the nasal chemosensory receptors and the OVN, so the therapeutically effective amounts when administered essentially only to the nasal chemosensory receptors will be perhaps 20 times lower. One skilled in the art will have no difficulty, considering that skill and this disclosure, in determining a therapeutically effective amount of 16a,17aepoxy-10p-hydroxyestr-4-en-3-one for other formulations. These doses, both nasal and direct vomeronasal/nasal chemosensory receptors, are well below any level that would cause a systemic effect other than those mediated through nasal chemosensory receptors, including VNO receptors.

The initial pharmacological response to nasal administration of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one occurs very rapidly, usually within seconds to one minute after administration. A more complete drug response occurs a little more slowly; but an effect on the migraine (or one or more migraine symptoms) is expected within 5 to 15 minutes. Due to the rapid onset of effect and safety of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one administered nasally, it is expected that the compound can be administered as needed, for example, immediately when a individual senses the onset of a migraine episode (such as a prodrome or aura), to preventively inhibit the migraine episode, or when the individual perceives a true symptom of a migraine episode (such as headache or other symptoms described in subsection titled "Migraine" from the background of the technique) to relieve and alleviate the symptoms of that episode. It is expected that the compound may be administered more than once, such as over a period of a few days, if first administered when a prodrome occurs to continue to prevent or minimize migraine or a symptom thereof, by scheduled administration at throughout the day, such as 2 to 6 times/day, for example, 3 to 5 times/day, such as 4 times/day. This scheduled administration can be done on a uniform schedule, for example, at 8 a.m. m., noon, 4 p.m. m. and at 8 p.m. m. (for administration 4 times a day), or on a non-uniform schedule where administration is selected to maximize at the time when the expected onset of migraine symptoms is most frequent or most intense, either in the population with migraine symptoms migraine or in the treated individual. So, for example, administration could be at 9 a.m., 3 p.m. m., 5 p.m. m. and 8 p.m. m. (again 4 times daily) to maximize administration at the time when the expected onset of symptoms is most frequent. Of course, even if scheduled administration is used, it is possible to administer the compound as needed if symptoms are still experienced. However, due to its rapid action, it is contemplated that its chronic use will not be necessary: treatment can be interrupted when the individual no longer feels a migraine symptom or the risk of suffering a migraine, and resumed when necessary.

Also, due to the rapid onset of effect of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one administered nasally, it is expected that the compound can be administered as an adjunct to conventional anti-migraine therapy (e.g. ., oral or injectable). For example, it can be used as a "rescue" medication in people who may still experience an episode of a migraine symptom even while receiving conventional anti-migraine therapy, to relieve and palliate the symptoms of that episode as needed.

Therefore, nasally administered 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one can be used acutely or intermittently, and alone or in combination with conventional anti-migraine therapy, in the treatment of migraine.

Example 1: Electrophysiological studies with 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one

16a,17a-Epoxy-10p-hydroxyestr-4-en-3-one induced inward currents in isolated human nasal chemosensory neurons and electrotonic depolarization of the chemosensory mucosa of the nasal septum: the first event in chemotransduction at peripheral receptors. The amplitude of this response increased depending on the concentration of the compound, with a maximum response at 10-7 to 10-6M. In vitro, there was no agonist or antagonist activity on glucocorticoid, estrogen, androgen, or progestin receptors, nor was there any affinity for indoleamine receptors, monoamines, ion channels, receptors, peptides, opioids, glutamate neurotransmitter, steroid hormones or glucocorticoid receptors, suggesting that the compound exerts its effects through specific receptors that are different from the other sites of union described.

Example 2: Preclinical studies with 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one

Acute and multiple-dose (28 days) toxicity studies in rats, mice, rabbits, and dogs with single (up to 100 pg/rat, 400 pg/rabbit, 600 pg/dog) and repeated (up to 50 pg/rat/dog) doses day, 300 pg/dog/day) in nasal and single doses (up to 2.5 mg/kg in rats, mice, rabbits) and repeated intravenous doses (up to 2.5 mg/kg/day in rats and rabbits) from 16a ,17a-epoxy-10p-hydroxyestr-4-en-3-one demonstrated that the compound was well tolerated in all species tested, with no deaths or adverse clinical signs or observed effects on laboratory or pathology parameters.

Genotoxicity testing revealed no evidence of mutagenic or clastogenic potential of the compound when examined in the Ames reverse mutation assay and the in vivo bone marrow micronucleus test. Reproductive toxicity studies in pregnant rabbits revealed no adverse effects on the parameters maternal or litter attributable to the compound at intravenous doses of up to 2.5 mg/kg/day administered during the period of organogenesis. Preclinical pharmacokinetic studies with the compound demonstrated very low systemic exposure when the compound was administered by repeated or single escalating nasal doses up to 100 pg/rat, 400 pg/rabbit, 600 pg/dog. When administered to rats, rabbits or dogs in repeated single intravenous doses up to 2.5 mg/kg, plasma concentrations of the compound were generally dose proportional and decreased rapidly.

Example 3: Preliminary human studies with 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one (predictive of efficacy)

Preliminary findings showed that nasal administration of microgram amounts of 16a,17aepoxy-10p-hydroxyestr-4-en-3-one to human volunteers of both sexes induced a concentration-dependent activation of the electrogram recorded at the mucosal surface. nasal chemosensory. The mean effective dose for this effect was 0.087 pg. The electrogram induced during nasal administration of 1.6 pg of 16a,17a-epoxy10p-hydroxyestr-4-en-3-one was followed rapidly (5-10 second latency) by a modulation of reflex activity integrated into the limbic system, hypothalamus and cerebral cortex. There was a significant increase in the amplitude of the depth of the inspiratory cycle of breathing and a decrease in respiratory frequency within the physiological range, an increase in the amplitude of skin conductance measured as electrodermal activity or dermolimbic reflex of the surface of the palm of the fourth and fifth fingers, a decrease in skeletal muscle tone (relaxation) measured from the electromyogram recorded transdermally from the chin muscles, and a decrease in core body temperature recorded from the external auditory canal. There were no significant changes in heart rate.

The effects of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one on physiological parameters are explained below:

(a) Decreased respiratory rate and increased depth of breathing result from decreased airway resistance induced by bronchiolar dilation. 16a,17a-Epoxy-10p-hydroxyestr-4-en-3-one decreased the tone of the parasympathetic system, resulting in increased sympathetic activity and stimulation of p2 adrenergic receptors in the smooth muscle of the bronchioles that induced bronchodilation;

(b) increased skin conductance amplitude is the result of increased skin secretions, which are produced by preponderance of sympathetic nervous system tone (or decreased parasympathetic tone);

(c) the decrease in body temperature is explained by increased activity of the posterior hypothalamus (adrenergic) and a decrease in parasympathetic tone (anterior hypothalamus). This effect was also demonstrated in menopausal women as a decrease in the number, severity, and bothersomeness of hot flashes after nasal administration of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one; and (d) decreased muscle tone or relaxation was induced through efferent limbic-hypothalamic neural connections with cortical areas.

Example 4: Human clinical studies with 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one (predictive of efficacy and safety)

In a group of 14 women of reproductive age, nasal administration of a nasal spray containing 0.5 μg of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one per administration (administration by a pump Aptar nasal spray 50 μl of a 10 μg/ml aqueous solution of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one with 2% propylene glycol and 2% ethanol), compared to vehicle alone, induced statistically significant decreases in respiratory rate, skeletal muscle tone, galvanic skin reflex, and core body temperature; as well as a non-statistically significant increase in heart rate.

In another study, also in women of reproductive age, nasal delivery of a nasal spray containing 1.6 μg of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one (one administration per nostril via a Aptar nasal spray pump of 50 μl of a 16 μg/ml aqueous solution of 16a,l7a-epoxy-10p-hydroxyestr-4-en-3-one with 2% propylene glycol and 2% ethanol) induced a rapid decrease (latency 0.5 to 4 minutes) at core body temperature of 1 ± 0.23°C that persisted for 9 ± 2.5 minutes. It also changed the tone of the sympathoadrenergic system (as assessed by measuring physiological sinus arrhythmia) within 5 minutes of administration, and the effect persisted for 15 to 20 minutes.

In a randomized, double-blind, placebo-controlled trial in women diagnosed with PMDD, nasal administration of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one induced significant improvements in hypothalamic health (fatigue, irritability , food craving), limbic system (mood swings, depression, lack of interest) and cortical behavioral symptoms (headache, tension). These improvements appeared within 30 minutes of single-dose nasal administration of the formulation and persisted for approximately 5 hours. Due to the excellent safety profile of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one and the absence of systemic exposure demonstrated in a pharmacokinetic bioavailability study, the medication was repeated up to 6 times daily. No serious adverse events were reported and side effects were minimal and similar to placebo administration.

Therefore, the nasal administration of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one from the onset of behavioral symptoms of PMDD (similar to the prodromes of migraine) activates the neuronal circuits in the areas limbic-hypothalamic areas of the brain that improve behavioral functioning (mood changes, irritability, tension, stress). This prevents increased tone of the parasympathetic system and the release of vasoactive and nociceptive molecules from the meningeal vessels, resulting in deactivation of the trigeminovascular pathway.

These effects, including especially a decrease in skeletal muscle tension, a decrease in the frequency of cutaneous galvanic reflex events, and a decrease in fatigue, headache, tension, depression, irritability/anger, anhedonia, and food cravings, are predictive of the efficacy and safety of nasal administration of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one in the treatment of migraine.

Example 5: Human clinical studies with 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one in patients with migraine (demonstrating efficacy and safety)

In a single-blind exploratory study, one control subject and two subjects with chronic migraine (diagnosed according to the International Classification of Headache Disorders, 3rd edition) with a history of regular migraine attacks lasting typically one to three days , participated in two identical study sessions one week apart, and subjects with migraine were instructed to participate during the first day of a migraine attack. Each subject received a baseline assessment using the Hamilton Anxiety Scale (HAM-A), a clinician-administered rating scale developed to quantify the severity of anxiety symptomatology, and the Hamilton Depression Rating Scale (HAM-D). ), a physician-administered rating scale developed to quantify the severity of depression; and asked to rate their migraine pain using a 6-point visual reference scale (VRS), with 0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain, 4 = very severe, 5 = the most intense pain imaginable. Each subject was then treated with a single nasal administration of a placebo formulation during the first study session, and with a single nasal administration of 6.4 pg of 16a,17a-epoxy-10p-hydroxyestr-4-en- 3-one during the second study session. After 15 minutes, each subject was asked to re-assess their pain level and underwent resting-state fMRI. They were then re-evaluated with the HAM-A and HAM-D scales. The study plans to have a total of 30 subjects.

The control subject was a 35-year-old woman who did not suffer from migraine, anxiety, or depression; The two subjects with migraine were a 38-year-old woman (with a 14-year history of migraine, 19 days/month of headache of which 9 days/month were severe, migraine with aura, anxiety and depression) and a 41-year-old man. (with a 5-year history of migraine, 13 days/month of headache of which 4 days/month were severe, and depression).

Nasal 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one was tolerated by all three subjects and no side effects or adverse effects were reported. Although both migraine subjects showed mild anxiety and depression at admission, nasal 16a,17aepoxy-10p-hydroxyestr-4-en-3-one significantly improved anxiety scores (p<0.01) and there was a trend of improvement in depression scores in both subjects, but it did not reach statistical significance. Nasal 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one produced a significant improvement in headache severity scores in subjects with migraine assessed using VRE, with a mean decrease of 2.5 compared to to placebo (p<0.01). Migraine patients showed an improvement in the functional connectivity of the brain areas studied: relative to placebo, nasal 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one decreased the functional connectivity of the hypothalamus with anterior orbital gyrus, right medial orbital gyrus and pons, increased functional connectivity of the amygdala with the anterior occipital lobe and right middle occipital lobe, decreased functional connectivity of the right thalamus with the left orbitofrontal cortex, superior parietal lobe , the left insular cortex and the left primary motor cortex, and increased functional connectivity with the left somatosensory cortex; which represents a trend towards the values of the healthy control subject.

These effects, including especially decreased pain, anxiety, and depression, of nasal administration of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one demonstrate the efficacy and safety of nasal administration of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one. 17a-epoxy-10p-hydroxyestr-4-en-3-one in the treatment of migraine.

Claims (15)

1. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use in the treatment of an individual suffering from migraine by nasal administration. 2. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 1, wherein nasal administration includes vomeronasal administration. 3. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 1 or 2, wherein the individual is a man. 4. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 1 or 2, wherein the individual is a woman. 5. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to any one of claims 1 to 4, wherein the 16a,17a-epoxy-10p-hydroxyestr-4-en- 3-one is administered at the onset of a migraine symptom. 6. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to any one of claims 1 to 4, wherein 16a,17a-epoxy-10p-hydroxyestr-4-en- 3-one is administered at the onset of a migraine prodrome or aura. 7. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 6, wherein the 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one is administered at the beginning of a migraine prodrome. 8. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 6, wherein the 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one is administered at the beginning of an aura. 9. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to any one of claims 1 to 8, wherein 16a,17a-epoxy-10p-hydroxyestr-4-en- 3-one is administered on a schedule during the day. 10. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 9 wherein the 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one is administered as 2 to 6 times a day, such as 3 to 5 times a day, such as 4 times a day. 11. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 9 or 10, wherein the administration of the 16a,17a-epoxy-10p-hydroxyestr-4-en- 3-one is chosen to maximize administration at the time when the expected onset of migraine symptoms is most frequent or most intense in the population with migraine symptoms, or in the individual being treated. 12. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to any one of claims 1 to 11, wherein 16a,17a-epoxy-10p-hydroxyestr-4-en- 3-one is administered in a pharmaceutical formulation. 13. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 12, wherein the pharmaceutical formulation is a nasal spray, such as an aqueous solution of 16a,17a-epoxy- 10p-hydroxyestr-4-en-3-one. 14. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to claim 13, wherein the content of 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one of the nasal spray is 0.8 μg to 19.2 μg per administration, such as 1.6 μg to 9.6 μg per administration, for example, 1.6 μg, 3.2 μg or 6.4 μg jg by administration. 15. 16a,17a-epoxy-10p-hydroxyestr-4-en-3-one for use according to any one of claims 1 to 14, wherein migraine is associated with previous head trauma.